Mediating Factors in the Association of Maternal Educational Level With Pregnancy Outcomes

Key Points Question Which pathways mediate the inequity in pregnancy health associated with low educational attainment? Findings In this cohort study of more than 3 million individuals, an association between genetically estimated lower educational attainment and increased risk of ectopic pregnancy, hyperemesis gravidarum, gestational diabetes, preeclampsia, preterm birth, and offspring low birth weight was observed. A sizeable portion of these associations were explained by targetable risk factors. Meaning These findings suggest that the association of socioeconomic inequalities with adverse pregnancy outcomes may be reduced by intervening for type 2 diabetes, body mass index, smoking, high-density lipoprotein cholesterol level, and systolic blood pressure.

This supplementary material has been provided by the authors to give readers additional information about their work.

Study Design
In a two-sample Mendelian randomization (MR) study, for a given single-nucleotide polymorphism (SNP) used as a genetic proxyor instrumentthe SNP-outcome association is divided by the SNP-exposure association to provide an estimate of the exposure-outcome association, often referred to as the Wald ratio. 1 Associations across multiple SNPs are pooled using meta-analytical approaches (Supplementary Figure 1).The steps of a two-sample MR are as follows: First, we identify genetic instruments of the exposure of interest (i.e., educational attainment), next we extract data on how these genetic instruments affect levels of the mediators (e.g., BMI) and outcomes (e.g., preeclampsia), and finally we run analyses as described below.
To limit the risk of confounding due to population stratification, only data from subjects of European ancestry were included. 1e summary level data used for this study were publicly available.Data from Steinthorsdottir et al 2 was obtained through application to the Wellcome Sanger Institute (https://ega-archive.org).Data were extracted between December 2022 and April 2023, and analyzed between January 2023 and June 2023.
The number of SNPs included as genetic instruments for educational attainment varied by outcome under study, from 1,294 for birth weight to 1,727 for T2DM.

Choice of Mediators
Based on our previous research on lipids and risk of preeclampsia, 3 we decided to evaluate HDL-C instead of non-HDL-C.To limit the number of potential mediators evaluated, and to focus on more specifically modifiable phenotypes that have strong genetic predictors, we did not evaluate sleep health, diet, or physical activity as mediators.

eAppendix. Clinical and Public Health Implications
Our study has several important contributions relevant to policy.First, our study strongly supports previous observations that low levels of education are associated with an increased risk of adverse pregnancy outcomes.This is important, because the triangulation of evidence between traditional observational studies and genetic epidemiological studieswith their different sources of biasunderscores that educational attainment is key for healthy pregnancies at the population level.Policies to facilitate access to continuing and higher education for all may thus improve pregnancy health.However, while the largest potential for improved equity is at the societal level, it can be challenging to improve educational attainment, and among those with low educational attainment it is crucial to identify targetable factors that may reduce the risk of adverse pregnancy outcomes.Optimizing all the cardiometabolic traits would considerably lower the risk of ectopic pregnancy, gestational diabetes and preeclampsia, but would have little effect on hyperemesis gravidarum.Subjects with little education and with an otherwise underlying susceptibility to a particular outcome (e.g., previous pelvic surgery leading to an increased risk of ectopic pregnancy) would benefit from more targeted lifestyle changes (e.g., quitting smoking).Finally, for all the evaluated pregnancy outcomes, except preeclampsia, the majority of the effect of educational attainment was mediated through other pathways than the cardiometabolic traits considered; identification of these other factors is important.From an equity perspective, knowledge about the mediating pathways may inform clinicians, public health officials and policy makers where we should prioritize to get closer to equal outcomes in pregnancy health regardless of socioeconomic background.

eFigure. Schematic Presentation of the Mendelian Randomization Design
Legend: Red arrow represents the causal effect of interest.For each genetic instrument, the causal effect is estimated by dividing the genetic variantoutcome association by the genetic variantexposure association.
For this estimate to be valid, three main assumptions need to be met: 1) The genetic variant is associated with the exposure; 2) the genetic variant is not associated with outcome via a confounder; and 3) the genetic variant does not directly affect the outcome.

Adverse pregnancy outcome
Educational attainment Genetic variant associated with higher educational attainment Confounders 1 2 Study Design and Choice of Mediators eAppendix.Clinical and Public Health Implications eTable 1. Overview of Analyses eTable 2. Univariable Mendelian Randomization Analyses of Educational Attainment on Pregnancy Outcomes eTable 3. Univariable Mendelian Randomization Analyses of Educational Attainment on Cardiometabolic Mediators eTable 4. Univariable Mendelian Randomization Analyses of Type 2 Diabetes on Pregnancy Outcomes eTable 5. Univariable Mendelian Randomization Analyses of Body Mass Index on Pregnancy Outcomes eTable 6. Univariable Mendelian Randomization Analyses of Smoking on Pregnancy Outcomes eTable 7. Univariable Mendelian Randomization Analyses of High-Density Lipoprotein Cholesterol Level on Pregnancy Outcomes eTable 8. Univariable Mendelian Randomization Analyses of Systolic Blood Pressure on Pregnancy Outcomes eFigure.Schematic Presentation of the Mendelian Randomization Design eReferences eMethods.

Grams (95% CI) P-value Grams (95% CI) P-value Grams (95% CI) P-value Grams (95% CI) P-value
2024 Rogne T et al.JAMA Network Open.Greatest statistical power.Assumes all genetic instruments to be valid.Used to estimate the total effect of educational attainment on adverse pregnancy outcomes.Weighted mode Provides reliable estimate as long as more genetic instruments estimate the true causal effect than estimate any other quantity.Robust to outlying genetic instruments.Weighted median Provides reliable estimate as long as most of the genetic instruments do not have pleiotropic effects.Robust to outlying genetic instruments.MR Egger Allows all genetic instruments to have pleiotropic effects as long as the pleiotropic effects on risk of adverse pregnancy outcomes are not correlated with the magnitude of the genetic variants' effects on educational attainment.Sensitive to outlying genetic instruments.Multivariable analysis Used to estimate the direct effect of educational attainment on adverse pregnancy outcomes, conditional on the other mediators included in the model.Univariable Mendelian Randomization Analyses of Educational Attainment on Cardiometabolic Mediators Univariable Mendelian Randomization Analyses of Body Mass Index on Pregnancy Outcomes Univariable Mendelian Randomization Analyses of High-Density Lipoprotein Cholesterol Level on Pregnancy Outcomes.Univariable Mendelian Randomization Analyses of Systolic Blood Pressure on Pregnancy Outcomes CI, confidence interval; OR, odds ratio; SNPs, single-nucleotide polymorphisms.©2024RogneTetal.JAMA Network Open.eTable 3.Betas reflect standard deviation units for all traits except for T2DM where it reflects log(odds ratio).BMI, body mass index; CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; SBP, systolic blood pressure; SNPs, single-nucleotide polymorphisms; T2DM, type 2 diabetes mellitus.eTable4.Univariable Mendelian Randomization Analyses of Type 2 Diabetes on Pregnancy Outcomes © 2024 Rogne T et al.JAMA Network Open.eTable 5. CI, confidence interval; OR, odds ratio; SNPs, single-nucleotide polymorphisms.eTable 6. Univariable Mendelian Randomization Analyses of Smoking on Pregnancy Outcomes © 2024 Rogne T et al.JAMA Network Open.eTable 7. CI, confidence interval; OR, odds ratio; SNPs, single-nucleotide polymorphisms.eTable 8. CI, confidence interval; OR, odds ratio; SNPs, single-nucleotide polymorphisms.